1. Field of the Invention
The present invention concerns an improved therapeutic regimen for the treatment of thrombolytic disorders, such as acute myocardial infarction (AMI). In particular, the present invention concerns the treatment of thrombolytic disorders, e.g. AMI with a combination of a tissue plaminogen activator (t-PA) variant having improved fibrin specificity and extended plasma half-life (when compared with wild-type human t-PA) and an anti-thrombin agent having anti-Xa and/or anti-IIa activity, such as a low molecular weight heparin.
2. Description of the Related Art
Thrombolytic therapy has been a major advance in the treatment of acute myocardial infarction (AMI). Thrombolytics can re-establish perfusion in occluded arteries, resulting in smaller infarct size, improved left ventricular function, and improved short and long-term survival. See e.g., Braunwald E., Circulation 79:441–1 (1989); Braunwald, N. Engl. J. Med. 329:1650–2 (1993); The GUSTO investigators. An international randomized trial comparing four thrombolytica strategies for acute myocardial infarction. N. Engl. J. Med. 329:673–82 (1993).
However, current regimens of thrombolytic-antithrombic therapy continue to be limited by failure of initial recanalization and reocclusion in about 40–45% of patients (Cannon et al., J. Am. Col. Cardiol. 24:1602–10 (1994); The GUSTO Angiographic Investigators, N. Engl. J. Med. 329:1615–22 (1993); Cannon and Braunwald, Acta Cardiol. 49:1–8 (1994)). In addition, intracranial hemorrhage can occur in over 0.9% of the patients treated with thrombolytics (ISIS-3 (Third International study of Infarct Survival) Collaborative Group, Lancet 339:753–70 (1992); The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators, N. Eng. J. Med. 335:775–82 (1996); ASSENT-II Investigators, Lancet 354:716–22 (1999)).
Attempts to increase the efficacy of thrombolytic therapy by increasing the dose of thrombolytic have been unsuccessful because of unacceptably high incidence of intracranial hemorrhage. Also, an important factor in reducing mortality associated with AMI is the reduction of time to reperfusion (Rawles, J., BMJ 312:212–15 (1996); Linderer et al., J. Am. Coll. Cardiol. 22:212–215 (1996); Weaver et al., JAMA 270:1211–16 (1993)). Guidelines concerning the treatment of AMI have suggested a target figure of 90 minutes for the maximum delay between the patient seeing help and receiving thrombolysis. Despite encouraging results, pre-hospital thrombolysis has not been widely implemented, and the delay from symptom onset to arrival to hospital, which constitutes about two thirds of the overall delay, remains a major impediment to optimal reperfusion. Accordingly, there is a great need for a thrombolytic regimen that allows early intervention, provides high efficacy, and carries low risk of bleeding side-effects.
A particularly successful t-PA variant is tenecteplase (TNKase™), a t-PA variant with extended half-life and improved fibrin specificity when compared to native human t-PA. TNKase™ (TNK-t-PA; T103N, N117Q, KHRR(296–299)AAAA t-PA) is a 527 amino acids long glycoprotein developed by Genentech, Inc., which obtained FDA approval on Jun. 2, 2000 for use in the reduction of mortality associated with acute myocardial infarction (AMI). TNKase™ (tenecteplase) is a derivative of wild-type human t-PA, which has a threonine (T) replaced by an asparagine at amino acid position 103, adding a glycosylation site at that position, an asparagine (N) replaced by glutamine at position 117, removing a glycosylation site at that position, and four amino acids, lysine (K); histidine (H), arginine (R), and arginine (R) replaced by four alanines (A,A,A,A) at amino acid positions 296–299. A large scale clinical trial (ASSENT-II) has shown TNKase™ (tenecteplase) to be the optimal thrombolytic agent, due to its ease of single-bolus administration, equivalent mortality to t-PA, and lower bleeding risk, as a result of its improved fibrin specificity (ASSENT-II Investigators, Lancet 354:716–22 (1999)). While of all thrombolytic agents tested, TNKase™ (tenecteplase) has been found to have the highest fibrin specificity, and its extended half-life allows single bolus dose administration, there is room for further improvement by way of improving efficacy without increasing the risk of side-effects, such as intracranial bleeding and stroke. For safety of a single bolus administration of tenecteplase see also Van de Werf et al., Am. Heart J. 137:786–91 (1999).